The importance of blood pressure thresholds versus predicted cardiovascular risk on subsequent rates of cardiovascular disease: a cohort study in English primary care

Summary Background For five decades, blood pressure lowering treatment has been recommended for patients with hypertension (currently defined as blood pressure of ≥140/90 mm Hg). In the past 20 years, guidelines for treatment began incorporating predicted absolute cardiovascular disease risk (predicted risk) and reducing blood pressure thresholds. The blood pressure threshold at which to start treatment has become a secondary consideration in some countries. We aimed to provide descriptive data to assess the relative importance of blood pressure thresholds versus predicted risk on the subsequent rate of cardiovascular disease to inform treatment decisions. Methods In this English population-based cohort study, we used linked data from the Clinical Practice Research Datalink (CPRD) GOLD, Hospital Episode Statistics Admitted Patient Care, and the Office for National Statistics mortality data, and area-based deprivation indices (Townsend scores). Eligible patients were aged 30–79 years on Jan 1, 2011 (cohort entry date) and could be linked to hospital, mortality, and deprivation data. Patients were followed up until death, end of CPRD follow-up, or Nov 31, 2018. We examined three outcomes: cardiovascular disease, markers of potential target organ damage, and incident dementia without a known cause. The rate of each outcome was estimated and stratified by systolic blood pressure and predicted 10-year risk of cardiovascular disease (QRISK2 algorithm). Findings Between Jan 1, 2011, and Nov 31, 2018, 1 098 991 patients were included in the cohort and followed up for a median of 4·3 years (IQR 2·6–6·0; total follow-up of 4·6 million person-years). Median age at entry was 52 years (IQR 42–62) and 629 711 (57·3%) patients were female. There were 51 996 cardiovascular disease events and the overall rate of cardiovascular disease was 11·2 per 1000 person-years (95% CI 11·1–11·3). Median QRISK2 10-year predicted risk was 4·6% (IQR 1·4–12·0) and mean systolic blood pressure before cohort entry was 129·1 mm Hg (SD 15·7). Within strata of predicted risk, the effect of increasing systolic blood pressure on outcomes was small. For example, in the group with 10·0–19·9% predicted risk, rates of all cardiovascular disease rose from 20·1 to 23·6 per 1000 person-years between systolic blood pressures less than 110 mm Hg and 180 and higher mm Hg. But among patients with systolic blood pressure 140·0–149·9 mm Hg, rates rose from 6·9 to 52·3 per 1000 person-years between those with less than 10·0% risk and those with 30·0% or higher predicted risk. Interpretation For a wide range of blood pressures, the rate of cardiovascular disease and effectiveness of blood pressure drug treatment was mainly determined by predicted risk, with blood pressure thresholds 140/90 mm Hg or 160/100 mm Hg—ubiquitous in most countries—adding little useful information. When medium-term predicted risk is low, there is no urgency to initiate drug treatment, allowing time to attempt non-pharmacological blood pressure reduction. Funding National Institute for Health Research.

Cardiovascular disease prior to cohort entry, n=145,836 Without a blood pressure record before cohort entry, n=300,416 Target organ damage prior to cohort entry, n=53,230 N=1,647,853 (n=822,417 men) (n=825,436 women) Appendix Figure 3. Proportion of events occurring in patients according to their systolic blood pressure and predicted ten year cardiovascular risk score at cohort entry. BP: blood pressure All cardiovascular disease includes all coronary heart disease, cerebrovascular disease, peripheral arterial disease and heart failure.
Appendix Figure 4. Number of events occurring in patients according to their systolic blood pressure and predicted ten year cardiovascular risk score at cohort entry. BP: blood pressure All cardiovascular disease includes all coronary heart disease, cerebrovascular disease, peripheral arterial disease and heart failure. Figure 5. Proportion of events occurring in patients according to their diastolic blood pressure and predicted ten year cardiovascular risk score at cohort entry. BP: blood pressure All cardiovascular disease includes all coronary heart disease, cerebrovascular disease, peripheral arterial disease and heart failure. Appendix Figure 6. Number of events occurring in patients according to their diastolic blood pressure and predicted ten year cardiovascular risk score at cohort entry. BP: blood pressure All cardiovascular disease includes all coronary heart disease, cerebrovascular disease, peripheral arterial disease and heart failure. Figure 7. Among patients who were (A) treated with blood pressure lowering at cohort entry and (B) not treated with blood pressure lowering at cohort entry, the rate (with 95% confidence interval) of cardiovascular disease, acute coronary syndrome, stroke, peripheral arterial disease, heart failure, haemorrhagic stroke, chronic kidney disease and dementia stratified by systolic blood pressure and predicted ten year cardiovascular disease risk (QRISK2) at cohort entry. BP: blood pressure *Note different scales on axes for all cardiovascular disease and haemorrhagic stroke. All cardiovascular disease includes all coronary heart disease, cerebrovascular disease, peripheral arterial disease and heart failure.

B. Women
Appendix Figure 8. Among (A) men and (B) women, the rate (with 95% confidence interval) of cardiovascular disease, acute coronary syndrome, stroke, peripheral arterial disease, heart failure, haemorrhagic stroke, chronic kidney disease and dementia stratified by systolic blood pressure and predicted ten year cardiovascular disease risk (QRISK2) at cohort entry. BP: blood pressure *Note different scales on axes for all cardiovascular disease and haemorrhagic stroke. All cardiovascular disease includes all coronary heart disease, cerebrovascular disease, peripheral arterial disease and heart failure.

A. Age under 60
B. Age 60 and over Appendix Figure 9. Among (A) aged under 60 and (B) aged 60 or over, the rate (with 95% confidence interval) of cardiovascular disease, acute coronary syndrome, stroke, peripheral arterial disease, heart failure, haemorrhagic stroke, chronic kidney disease and dementia stratified by systolic blood pressure and predicted ten year cardiovascular disease risk (QRISK2) at cohort entry. BP: blood pressure *Note different scales on axes for all cardiovascular disease and haemorrhagic stroke. All cardiovascular disease includes all coronary heart disease, cerebrovascular disease, peripheral arterial disease and heart failure.
A. Diabetes at cohort entry B. No diabetes at cohort entry Appendix Figure 10. Among patients with (A) diabetes at cohort entry and (B) no diabetes at cohort entry, the rate (with 95% confidence interval) of cardiovascular disease, acute coronary syndrome, stroke, peripheral arterial disease, heart failure, haemorrhagic stroke, chronic kidney disease and dementia stratified by systolic blood pressure and predicted ten year cardiovascular disease risk (QRISK2) at cohort entry. BP: blood pressure *Note different scales on axes for all cardiovascular disease and haemorrhagic stroke. All cardiovascular disease includes all coronary heart disease, cerebrovascular disease, peripheral arterial disease and heart failure.
Appendix Figure 11. Rates of chronic kidney disease and eGFR<60ml/min/1.73 m2 during follow-up, stratified by systolic blood pressure and predicted ten year cardiovascular disease risk (QRISK2) at cohort entry. BP: blood pressure Appendix Figure 12. The rate (with 95% confidence interval) of cardiovascular disease, acute coronary syndrome, stroke, peripheral arterial disease, heart failure, haemorrhagic stroke, chronic kidney disease and dementia stratified by most recent systolic blood pressure and predicted ten year cardiovascular disease risk (QRISK2) at cohort entry. BP: blood pressure * All cardiovascular disease includes all coronary heart disease, cerebrovascular disease, peripheral arterial disease and heart failure.
Diastolic blood pressure Figure 13. Rate (with 95% confidence interval) of cardiovascular disease, acute coronary syndrome, stroke, peripheral arterial disease, heart failure, haemorrhagic stroke, chronic kidney disease and dementia stratified by diastolic blood pressure and predicted ten year cardiovascular disease risk (QRISK2) at cohort entry. BP: blood pressure *Note different scales on axes for all cardiovascular disease and haemorrhagic stroke. All cardiovascular disease includes all coronary heart disease, cerebrovascular disease, peripheral arterial disease and heart failure.

Calculation of estimated number needed to treat (NNT) to prevent one cardiovascular disease event NNT Methods
Based on a recent meta-analysis of 74 trials, those with systolic blood pressures 160mmHg and above were assumed to gain a 22% treatment benefit, while those with blood pressures 140mmHg-159.9mmHg were assumed to have a 12% benefit. Patients with blood pressures below 140mmHg were assumed not to benefit from blood pressure lowering. 1 Calculation of NNTs was performed using direct standardization by treatment status, assuming those treated at cohort entry had already received treatment benefit, while those untreated at cohort entry were yet to benefit from treatment. 2 NNTs were presented for all cardiovascular disease outcomes and for each level of blood pressure (≥140mmHg) and predicted risk.

Estimated numbers needed to treat (NNT) to prevent an event
Restricting to patients with systolic blood pressures of 140mmHg and above, the NNTs for five years to prevent one cardiovascular disease outcome are shown in Figure 3. The NNT falls with increasing blood pressure, but much greater differences are observed between categories of predicted risk. For example, among patients with systolic blood pressure 160-169.9mmHg and predicted risk <10% (who would be treated under all global guidelines), we would need to treat an estimated 432 patients for five years to prevent one cardiovascular disease event. For patients with blood pressure 140-149.9mmHg but ≥30% predicted risk, we would need to treat an estimated 160 patients for five years to prevent one cardiovascular disease event. Figure 3. Number needed to treat for five years to prevent one cardiovascular disease, acute coronary syndrome, stroke, peripheral arterial disease, heart failure, haemorrhagic stroke, stratified by systolic blood pressure and predicted ten year cardiovascular disease risk (QRISK2) at cohort entry. All NNTs are plotted on the log scale. Based on effectiveness estimates from Brunstrom (blood pressure lowering treatment reduces cardiovascular disease by 22% if ³160mmHg, but 12% if <160mmHg) 1 BP: blood pressure *Note the different scale on axis for all cardiovascular disease. All cardiovascular disease includes all coronary heart disease, cerebrovascular disease, peripheral arterial disease and heart failure.

NNT Discussion
Three strong assumptions are required in our calculation of the number needed to treat, which were based on the rates among treated and untreated patients. First, that those on treatment all received full benefit from treatment, as estimated in meta-analysis. 1 This is likely to be an overestimation due to suboptimal adherence. 3,4 This would have made the outcome rates higher in the treated group than in a scenario of perfect adherence, and would have led to smaller differences between treated and untreated groups. Second, that those who were untreated did not receive any benefit from treatment. Our data showed that a large proportion of those untreated at baseline did subsequently receive treatment, which means that we may have overestimated the benefit among these patients. Third, that the effect of blood pressure lowering is the same across different cardiovascular disease outcomes. The effectiveness estimates used in the present study were based on those for major cardiovascular disease events 1 and it is unclear whether this would translate to all forms of acute and chronic cardiovascular disease.
The RECORD statement -checklist of items, extended from the STROBE statement, that should be reported in observational studies using routinely collected health data.